1. Field of the Invention
This invention relates to the synthesis of aminoalkyl phenyl selenides useful for the treatment of hypertension and nervous system dysfunctions.
2. Description of the Prior Art
Phenolic aryl-seleno and aryl-thio compounds and other selenide and sulfide derivatives have been disclosed for use as photographic couplers. Lau, Phillip T. S., Arylthio (or seleno, or sulfonyl) Methyl-Substituted Phenolic Compounds As Photographic Couplers, Chem. Abstracts 80: 82391. Neither the structures, nor the use disclosed by Lau are related to the compositions of the present invention.
May et al., U.S. Pat. No. 4,415,591 of Nov. 15, 1983, which patent is assigned in common herewith, the subject matter of which is incorporated herein by reference, discloses a method for treating hypertension involving the administration of aminoalkyl phenyl sulfide derivatives; there is also disclosed a method for evaluating the hypotensive potential of these compounds through the rate of enzymatic oxygenation by dopamine-beta-hydroxylase in the presence of an electron donor such as hexacyanoferrate (II) or ascorbic acid; and pharmaceutical compositions are also disclosed which comprise aminoalkyl phenyl sulfide or a salt thereof in amount effective for treatment of hypertension, a monoamine oxidase inhibitor and a nontoxic excipient.
As compared with the May et al. patent, this invention involves specifically different pharmaceutical compounds namely, aminoalkyl phenyl selenides and salts thereof, which have been found not only to cause substantial systemic blood pressure reduction, but may also provide potent clinical benefits with respect to nervous system dysfunctions and, in particular due to the unusual electrochemical properties of the selenoxide compound produced by the enzymatic oxygenation of the selenide, to enable reversible inhibition of the function of adrenergic neurons. This reversible inhibition is due to depletion of intracellular ascorbate, as more fully described below in the Detailed Description of the Invention and Preferred Embodiments.
While organosulfur chemistry is paralleled in a number of aspects by organoselenium chemistry, the facility of oxidation and reduction reactions can differ greatly. Riech, H. J. (1978), Oxidation in Organic Chemistry (Trahanovsky, W. ed.), Part C. pp 1-129, Academic Press, London and New York. For example, it has been reported that the monooxygenase activity of Aspergillus niger does not produce selenoxides from selenide substrates, despite the ready sulfoxidation of sulfides under the same conditions. The invention herein is believed to be the first example of selenoxidation by a specific monooxygenase, namely, dopamine-beta-hydroxylase.
The compounds of this invention, acting as substrates for the enzyme dopamine-beta-hydroxylase, consume two equivalents of ascorbic acid in the normal oxygenation process of dopamine-beta-hydroxylase. However, due to the unusual electrochemical properties of the resultant selenoxide product, spontaneous consumption of additional equivalents of ascorbic acid accompanies the reduction of this selenoxide product back to the original enzyme substrate form (e.g., back to the selenide). Thus, it is suggested that the infusion of a chosen derivative of this invention as the enzyme substrate results in an oxygenation/reduction cycle initiated and sustained by the target enzyme dopamine-beta-hydroxylase, which operates at the expense of intracellular ascorbic acid stores. This process can be used pharmaceutically to inhibit (reversibly) the function of adrenergic neurons in several locations in the body, including the central nervous system, the peripheral nervous system, and the adrenal glands. This result is highly unexpected and appears to result from and be limited to the phenyl selenides of this invention.
The prior art does not teach the aminoalkyl phenyl selenides or pharmaceutically acceptable salts thereof, nor the unexpected depletion of intracellular ascorbic acid which is characteristic of this invention.